Structural, Biophysical, and Biochemical Elucidation of the SARS-CoV-2 Nonstructural Protein 3 Macro Domain

ACS Infect Dis. 2020 Nov 13;6(11):2970-2978. doi: 10.1021/acsinfecdis.0c00441. Epub 2020 Oct 5.


The pandemic outbreak of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened the global public health and economy since late December 2019. SARS-CoV-2 encodes the conserved macro domain within nonstructural protein 3, which may reverse cellular ADP-ribosylation and potentially cut the signal of a viral infection in the cell. Herein, we report that the SARS-CoV-2 macro domain was examined as a poly-ADP-ribose (ADPR) binding module and possessed mono-ADPR cleavage enzyme activity. After confirming the ADPR binding ability via a biophysical approach, the X-ray crystal structure of the SARS-CoV-2 macro domain was determined and structurally compared with those of other viruses. This study provides structural, biophysical, and biochemical bases to further evaluate the role of the SARS-CoV-2 macro domain in the host response via ADP-ribose binding but also as a potential target for drug design against COVID-19.

Keywords: ADP-ribose; COVID-19; SARS-CoV-2; crystal structure; macro domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism
  • Antiviral Agents / pharmacology
  • Betacoronavirus / metabolism*
  • COVID-19
  • Coronavirus Infections / virology*
  • Drug Design
  • Humans
  • Pandemics
  • Pneumonia, Viral / virology*
  • Protein Conformation
  • Protein Domains
  • SARS-CoV-2
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism*


  • Antiviral Agents
  • Viral Nonstructural Proteins
  • Adenosine Diphosphate Ribose